Cholestenoic acids

Macrophages and cytokines can also influence lipoprotein metabolism [139], Grove et al. indicated that macrophages can secrete several proteins, including 27-oxygenated metabolites of cholesterol, that upregulate LDL receptors in HepG2 cells [140], This mechanism was compared with the classical HDL-dependent reverse cholesterol transport. With albumin as extracellular acceptor, the major secreted product was 3-/3-hydroxy-5-cholestenoic acid with HDL as acceptor, 27-hydroxycholesterol was the major secreted product [140, 141]. 

Two other new nuclear receptors have been shown to increase epidermal differentiation the LXR and the FXR. Farnesol and juvenile hormone activate the FXR leading to improved epidermal differentiation. Two genes encode for the LXR proteins, LXR alpha and LXR beta, and both are activated by various oxysterols the most potent being 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 24(S) 25-epoxycholesterol and 7-hydroxy cholesterol. Cholestenoic acid also acts on this receptor. In vitro these agents also increased epidermal filaggrin levels.129,130... 

Oxysterols have diverse roles in cholesterol efflux, a critical topic in foam cell biology. On the one hand, cells incubated with 7-ketocholesterol and 25-hydroxycholesterol have decreased cholesterol efflux. Possible mechanisms include inhibition of membrane desorption of cholesterol or phospholipids or, as mentioned above, inhibition of lysosomal sphingomyelinase leading to lysosomal sequestration of cholesterol (M. Aviram, 1995). On the other hand, the conversion of cholesterol by macrophage sterol 27-hydroxylase to 27-hydroxycholesterol and 3[l-hydroxy-5-cholestenoic acid, which are efficiently effluxed from cells, has been proposed to promote sterol efflux from foam cells (1. Bjorkhem,... 

With respect to the oxidation of the side chain in chenodeoxycholic acid formation, it may be inferred from the early studies with mitochondrial preparations that it involves an co-oxidation followed by a / -oxidation (cf. Section IIB). More direct evidence has been presented by Dean and White-house (87,91), who showed that mitochondrial preparations from rat liver catalyze the oxidation of 5-cholestene-3/ ,26-diol into 3/ -hydroxy-5-choles-tenoic acid and the formation of propionic acid from 3/5-hydroxy-5-choles-tenoic acid. Mitropoulos and Myant (97) have shown that mitochondrial preparations from rat liver catalyze the conversion of cholesterol into 5-cholestene-3/ ,26-diol, 3/ -hydroxy-5-cholestenoic acid, 3/5-hydroxy-5-chole-noic acid, lithocholic acid, and chenodeoxycholic acid (Fig. 5). Additional evidence for a pathway to chenodeoxycholic acid involving the successive, intermediary formation of above-mentioned compounds is provided by the finding that 3/ -hydroxy-5-cholenoic acid is converted into lithocholic acid and chenodeoxycholic acid by mitochondrial preparations (98). 

Fig. 5. Conversion of cholesterol into chenodeoxycholic acid by means of the intermediary formation of lithocholic acid. I, Cholesterol XVI, 5-cholestene-3ft26-diol XX, chenodeoxycholic acid XXI, 3j5-hydroxy-5-cholestenoic acid XXII, 3/ -hydroxy-5-cholenoic acid XXIII, lithocholic acid.

Even when adopting a targeted approach, the coverage of lipids in a specific class can still be restricted by the dominance of a few very abundant lipids. This may be the case for steroid analysis where cholesterol is often the most abundant steroid by two orders of magnitude. This problem can be minimized by subdivision of the steroid class according to hydropho-bicity where cholesterol and more hydrophobic steroids represent one class, and oxysterols (oxidized forms of cholesterol and its precursors) and less hydrophobic metabolites represent a second class [45]. This is an approach we adopted for the analysis of steroid sulphates and bile acid/ alcohol conjugates by shotgun steroidomics, and in our LC-ESl-MS/MS work on oxysterols and cholestenoic acids in brain [46,47], plasma [48], and cerebrospinal fluid (CSF) [49]. 

Axelson, M., Mork, B., Sjovall, I (1988) Occurrence of 3 beta-hydroxy-5-cholestenoic acid, 3 beta,7 alpha-dihydroxy-5-cholestenoic acid, and 7 alpha-hydroxy-3-oxo-4-cholestenoic acid as normal constituents in human blood. J. Lipid Res.,29(5), 629-641. 

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